Multivariate, Multi-omic Analysis in 799,429 Individuals Identifies 134 Loci Associated with Somatoform Traits.

Area of Science:

• Genetics
• Psychiatry
• Computational Biology

Background:

• Somatoform traits, characterized by physical symptoms without clear medical causes, are common and clinically challenging.
• Understanding the genetic architecture of somatoform disorders is crucial for advancing diagnostic and therapeutic strategies.

Purpose of the Study:

• To investigate the genetic basis of somatoform traits using a large-scale genome-wide association study (GWAS) and multi-omic analyses.
• To identify genetic loci, biological pathways, and potential therapeutic targets associated with a common somatoform factor.

Main Methods:

• Multivariate genome-wide association study (GWAS) and multi-omic analysis in 799,429 individuals of European ancestry.
• Genomic structural equation modeling to identify loci associated with a somatoform common factor.
• Gene-property analyses, drug repurposing, and Mendelian randomization to explore biological mechanisms and therapeutic potential.

Main Results:

• Identified 134 loci associated with a somatoform common factor, including 8 novel loci.
• Highlighted enrichment of genes involved in synaptic transmission and brain gene expression.
• Found substantial genetic overlap with psychopathology factors and associations with obesity, Type 2 diabetes, and mood/anxiety disorders.
• Suggested MEK inhibitors as potential therapeutics and identified protective effects of gut microbiota, such as *Ruminococcus bromii*.

Conclusions:

• The study elucidates the complex genetic architecture of somatoform traits, revealing significant polygenic overlap with psychiatric disorders.
• Identified novel genetic loci and biological pathways, offering potential targets for drug repurposing and novel therapeutic strategies.
• Provides biological insights into the etiology of somatoform traits, paving the way for improved clinical management.